Long acting steroid compounds



May 1, 1962 c. H. GLEASON LONG ACTING STEROID COMPOUNDS 2 Sheets-Sheet 2 Filed May 2, 1958 ON 2 a.

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flue/air C L flAf/VCE fl. 61.545 a! MM, 40% v United States Patent C) ice 3,032,469 LONG ACTING STEROID COMPOUNDS Clarence H. Gleason, Montreal, Quebec, Canada, assignor to Charles E. Frosst & Company, Montreal, Quebec, Canada, a corporation of Quebec Filed May 2, 1958, Ser. No. 732,490 4 Claims. (Cl. 167-65) The present invention relates to novel biologically active steroid compounds having strongly marked protracted efiect. Moreparticularly, it relates to hydrazone derivatives of steroid esters.

In accordance with the present invention, there is now provided a new series of biologically long-acting steroid hormone derivatives having the general formula:

wherein R is a radical of the general formula: I

Phenyl wherein R is selected from the group consisting of H and phenyl radicals and R is selected from the group consisting of hydrogen and hydroxy radicals.

is a cyclopentanohydrophenanthrene nucleus to which is linked a hydrazone radical and the 0R group is a group which is positioned in at least one of the positions -3, -17 and -2l of the cyclopentanohydrophenanthrene nucleus A and R is an acyl radical of a monocarboxylic acid containing from two to ten carbon atoms and selected from the group consisting of aliphatic hydrocarbon acids, cycloaliphatic hydrocarbon acids and benzoic acid.

These new steroid hormone derivatives are obtained by the reaction of a keto-steroid of the formula O=...A...OR

RNHN=...A...OR

In order to fully understand the scope of the present invention, the novel hydrazones corresponding to the following general formulae may !be obtained:

C H3 0 H: OHIO R; R, $1. CH, Big 3 11 RNH-N: ENEM- 3,032,469 Patented May 1, 1962 Rio @g R, and R are as defined above,

R is a radical selected from the group consisting of hydrogen and methyl R is a radical selected from the group consisting of hydrogen, lower alkyl radical and an alkynyl radical of from 2 to 6 carbon atoms R is a radical selected from the group consisting of hydrogen, hydroxy and --OR R is a radical selected from the group consisting of hydrogen, and lower alkyl R is an alkynyl radical of from two to six carbon atoms X is a radical selected from the group consisting of CH C=O, and CHOH radicals Y is a radical selected from the group consisting of halogen and hydrogen, and

Z is a radical selected from the group consisting of CH and CHOH.

The choice of the starting steroid is predicated on the presence of a reactive keto-group in positions 3- or 17- and a hydroxyl group in positions 17- or 3- and in some compounds such as those of group IV in the 21-position, which can be subsequently converted to an ester group by reaction with an appropriate esterifying agent.

As an example of the starting compounds suitable for obtaining the hydrazones of group I, there may be mentioned the 17-esters of testosterone, for example,

RNHNQU wherein Ai iom l testosterone-17-propionate, testosterone-17-enanthate, testosterone-17-cyclopentylpropionate, testosterone-17-benzoate; the 17a-alkynyl-17-esters of testosterone such as 17u-ethinyl-l7-acetate testosterone, 17u-ethinyl-l7-enanthate testosterone, 17a-ethinyl-17-cyclopentylpropionate-testosterone, 17a-ethinyl-l7-benzoate-testosterone, 17a-propargyl-17-propionate-testosterone, 17a-propargyl-17-pelargonate-testosterone, 17u-propargyl-17-cyclohexylpropionate-testosterone, 17 a-propargyl-17-benzoate-testosterone; the 17oz-3lkYl-17-6st6ls of testosterone such as 17u-methyl-17-propionate-testosterone, 17a-methyl-17-caproate-testosterone, 17a-methyl-17-enanthate-testosterone, 17a-methyl-17-cyclopentylformate-testosterone, '17a-methyl-l7-cycloheptylformate-testosterone, 17-ethyl-17-butyrate-testosterone,

17-ethyl-17 valerianate-testosterone,

17-ethyl-17-hexahydrobenzoate-testosterone,

17-ethyl-17-trimethylacetate-testosterone,

17-ethyl-17-benzoate-testosterone; the

19-nor-testosterone-17-esters, for example,

19-nor-testosterone-17-acetate,

l9-nor-testosterone-17-isobutyrate,

19-nor-test0sterone-17-cyclopentylacetate,

19-n0r-testosterone-17-cyclopropylforrnate,

19-nor-testosterone-17-benzoate; the

17a-alkynyl-17-esters-19-nor-testosterone, such as 17a-ethinyl-17-propionate-19-nor-testosterone,

17a-ethinyl-17-enanthate-19-nor-testosterone,

17a-ethinyl-17-cyclopentylpropionate-19-nortestosterone,

17a-ethinyl-17-benzoate-19-nor-testosterone,

17a-propargyl-17-propionate-19-nor-testosterone,

17a-propargyl-17-pe1argonate-19-nor-testosterone,

17a-propargyl-17-cyclohexylpropionate-1Q-nortestosterone, and

17a-propargyl-17-benzoate-19-nor-testosterone; the

1 1,6-hydroxy-9m-ha1o-17-a1kyl-17-esters-testosterone such as 1 lfi-hydroxy-9a-fiuoro-17-methyl-17-propionatetestosterone,

1 1 3-hydroxy-9x-fluoro-17-methy1-17-enanthate testosterone,

1 1B-hydroxy-9a-fluoro-17-methyl-17-caproatetestosterone,

1 1fl-hydroxy-9u-fluoro4 7-methyl- 17-cyclop entylacetatetestosterone,

1 1 fi-hydroxy-9 OL-flIlOI'O- 17-n1ethy1-1 7-benzoatetestosterone, and

11-keto-9a-halo-17-a1kyl-17 esters-testosterone, for

example 1 1-keto-9a-fiuoro-17-methyl-17-propionate-testosterone,

1 1-keto-9u-fluo-ro-17-rnethyl-17-cyclopentylpropionate testosterone and 1 l-keto-9d-fiuoro- 17 -methy1-17-benz oate, and other derivatives thereof.

When reacting the above starting materials withv a hydrazide of the formula RNHNH the corresponding hydrazones are obtained: the 3-hydrazones -17-esters of testosterone, for example,

3-benzi1ic acid hydrazone-testosterone-l7-propionate,

3-mandelic acid hydrazone-testosterone-l7-enanthate,

3-phenylacetic acid hydrazone-testosterone-1-7- cyclopentylpropionate,

3-diphenylacetic acid hydrazone-testosterone-17- benzoate; the

3 -hydrazones-17a a1kynyl-17-esters of testosterone such 3-benzilic acid hydrazone-17a-ethinyl-17-acetate testosterone,

3 mandelic acid hydrazone l7av-ethinyl-l7-enanthate testosterone,

3-phenylacetic acid hydrazone-17u-ethinyl 17-cyclopent ylpropionate-testosterone,

3-diphenylacetic acid hydrazone-l7a-ethinyl-l7-benzoatetestosterone,

3-benzilic acid hydrazone-17a-propargyl-17-propionatetestosterone,

S-mandelic acid hydrazone-lh-propargyl-17-pelargonatetestosterone,

3-phenylacetic acid hydrazone-17ot-propargyl-17rcyclohexylpropionatetestosterone,

3-dipheny1acetic acid hydrazone l7ot-propargyl-17-benzoate-testosterone; the

3-hydrazones-17a-al-kyl-17-esters of testosterone, such as B-benzilic acid hydrazone-17a-methyl-17-propionatetestosterone,

B-rnandelic acid hydrazone-Hot-methyl-17-caproate-testoterone,

3-pheny1acetic acid hydrazone-lh-methyl-17-enanthatetestosterone,

S-diphenylacetic acid hydrazone 17a methy1-17-cyclopentyl-formate-testosterone,

3-benzi1ic acid hydrazone 17oz methyl 17-cycloheptylformate-testosterone,

3-mar1delic acid hydraZone-17-ethyl-l7-butyrate-testosterone,

3 phenylacetic acid hydrazone 17-ethy1-17-valerianatetestosterone,

3-diphenylacetic acid hydrazone-17-ethy1-17-hexahydrobenzoate testosterone,

3-benzi1ic acid hydrazone-17aethyl-1 7-trimethylacetatetestosterone,

3-mandelic acid hydrazone-lj-ethyl-IZ-benzoate-testosterone; the

3-hydrazones-19-nor-testosterone-17-esters, for example,

3-benzilic acid hydrazone-1 9-nor-testosterone-17-acetate,

3 mandelic acid hydrazone 19-nor-testosterone-17-isobutyrate,

3 -phenylacetic acid hydrazone,-19-nor-testosterone-17- cyclopentylacetate,

3-diphenylacetic acid hydrazone-19-nor-testosterone-17- cyclopropylformate,

3-benzilic acid hydrazone-l9-nor-testosterone-17-benzoate; the

3-hydrazones-17u-alkynyl-17-esters-19-nortestosterone, such as 3-benzilic acid hydrazone-17a-ethinyl-17-propionate-l9- nor testosterone,

S-mandelic acid hydrazone-17a-ethinyl-17enanthate-19-.

nor testosterone,

3 phenylacetic acid hydrazone 17a ethinyl=17 -cyclo-.

pentylpropionate-l9-nor-testosterone,

B-diphenylacetic acid hydrazone-17a-ethinyl-17- benzoate- 19-n0r-testosterone,

3-benzilic acid hydrazone-17u-propargyl-17-propionate- 19-nor-testosterone,

3-phenylaeetic acid hydrazone-17a-propargy1-17 pe1arg0- nate-l9-nor-testosterone,

3-diphenylacetic acid hydrazone-17a-propargyl-17-cyc1oa hexylpropionate-l9,-nor-testosterone and 3-benzilic acid hydrazone-17a-propargyl-17-benzoate-19- nor-testosterone; the

3-hydrazones-1 1B-hydroxy-9m-halo-1-7-alky1-17-esterstestosterone, such as 3-benzilic acid hydrazone hydroxy 9a-fluoro-17- methyl-17-propionate-testosterone,

3-mandelic acid hydrazone 11B hydroxy-9a-fluoro-17- methy1-17-enanthate testosterone,

3-phenylacetic acid hydrazone-1l/3-hydroxyr9u-fiuoro-17- methyl-17-caproate-testosterone,

3-diphenylacetic acid hydrazone-11B-hydroxy-9a-fiuoro- 17-methyl-17-cyclopentylacetate-testosterone,

3-benzilic acid hydrazone 11B hydroxy 9a-flI1OIO-17- methyl-17B-cyclobutylpropionate-testosterone,

3 mandelic acid hydrazone 11/8 hYdlOXY-9oc-fill0TO-17- methyl-17-benzoate-testosterone, and

3-hydrazones-11-keto-9u-halo-17-a1ky1-17-esters:

testosterone, for example,

3-benzilic acid hydrazone 11 keto-9a-fiuoro-17-methy1- 17-pr0pionate-testosterone,

3-mandelic acid hydrazone-11-keto-9x-fluoro-17-methyl- 17-cyclopentylpropionate-testosterone and 3-phenylacetic acid hydrazone-11 keto 9a fluoro-17- methyl-17-benzoate, and derivatives thereof.

As an example of suitable starting materials for obtaining the hydrazones of'group II, there may be mentioned the A -pregnenes, such as prednisoloneor prednisone- 21-esters, for example,

prednisone-Z l -acetate, prednisone-2 1 -butyrate,

prednisone-Z1B-cyclopentylpropionate, prednisone-Zlfi-hexahydrobenzoate, prednisone-ZlB-benzoate, prednisolone-Zl-propionate, prednisolone-2l-enanthate, preduisolone-2l-hexahydrobenzoate, prednisolone-Zl-benzoate and derivatives thereof such as 9u-fluoro-16a-hydroxy-prednisolone-2l-propionate, 9a-fluoro-16u-hydroxy-prednisolone-2l-butyrate, 9a-fluoro-16a-hydroxy-prednisolone-21- cyclopentylpropionate and 9u-fiuoro-l6ot-hydroxy-prednisolone-21- benzoate; and 6-ot-methyl-prednisolone-2l-esters, for example, 6u-methyl-prednisolone-2l-acetate, 6ot-methyl-prednisolone2l-butyrate, 6u-methyl-prednisolone-21-enanthate, 6u-methyl-prednisolone-21-cyclopentylpropionate, and 6a-methy1-prednisolone-2l-benzoate.

When reacting these starting materials with a hydrazide of the formula RNHNH there are obtained the following hydrazones: the 3-hydrazones-prednis'oloneor prednisone-Zl-esters, for example, 3-benzilic acid hydrazone-prednisone-Z1-acetate,- S-mandelic acid hydrazone-prednisone-Zl-butyrate,

3 phenylacetic acid hydrazone prednisone 21p-cyclopentylpropionate,

3-diphenylacetic acid hydrazone-prednisone-2lp-hexahydrobenzoate,

3-benzilic acid hydrazone-prednisone-Z1/3-benzoate,

3-mandelic acid hydrazone-prednisolone-Z1-propionate,

3-phenylacetic acid hydrazone-prednisolone-2l-enanthate,

3-diphenylacetic acid hydrazone-prednisolone-2l-hexahydrobenzoate,

3-benzilic acid hydrazone-prednisolone-2l-benzoate, and

derivatives thereof such as 3-benzilic acid hydrazone-9ot-fluoro-16uhydroxy-prednisolone-Zl-propionate,

S-mandelic acid hydrazone-9ot-fiuoro-16ahydroxy-prednisolone-Zl-butyrate, 3-phenylacetic acid hydrazone 90c fiuoro-16a-hydroxyprednisolone-2l-cyclopentylpropionate and 3-diphenylacetic acid hydrazone-9a-fluoro-l6a-hydroxyprednisolone-Zl-benzoate and 3--hydrazones-6a-methyl-prednisolone-2l-esters, for example, 3-benzi1ic acid hydrazoneacetate, 3-rnandelic acid hydrazone-Gan-methyl-prednisolone-Z1- butyrate, 3-phenylacetic acid hydrazone-6a-methyl-prednisolone- ZI-enanthate, 3-diphenylacetic acid hydrazone-6a-methyl-prednisolone- 2l-cyclopentylpropionate, and B-phenylacetic acid hydrazones-6a-methyl-prednisolone- 21-benzoate.

As an example of suitable starting materials for obtaining the-hydrazones of group III, there may be mentioned the 17m-hydroxy-esters of progesterone, such as 17a-caproate progesterone, l7a-butyrate progesterone, l7ot-enanthate progesterone, and derivatives thereof.

When reacting these starting materials with a hydrazide of the formula RNHNH there are obtained the following hydrazones: the 3-hydrazones-l7ot-hydroxy-esters of progesterone such as S-benzilic acid hydrazone-17ot-caproate progesterone, 3-mandelic acid hydrazone-17a-butyrate progesterone, 3 -phenylacetic acid hydrazone17-aenanthate progesterone, and derivatives thereof.

As an example of suitable starting materials for obtaining the hydrazones of group IV, there may be mentioned desoXycorticosterone-2l-esters such as desoxycorticosterone-Zl-enanthate and desoxycorticosterone-21-trimethylacetate; cortisone-Zl-esters such as 600 methyl-prednisolone-Zlcortisone-Zl-butyrate, cortisone-Zl-enanthate,

6 cortisone-Zl-pelargonate, cortisone-2l-hexahydrobenzoate, cortisone-Zl-benzoate; hydrocortisone-Zl-esters such as hydrocortisone-Zl-enanthate, hydrocortisone-Zl-hexahydrobenzoate, hydrocortisone-2l benzoate and derivatives thereof, such as 9a-fluoro-hydrocortisone-Zl-acetate, 9a-fluoro-hydrocortisone-2l-butyrate, 9a-fluoro-hydrocortisone-2l-enanthate, 9a-fiuoro-hydrocortisone-2l-cyclohexylformate, 9u-fluoro-hydrocortisone-2l-benzoate; and 9a-fluoro-cortisone-2l-propionate, 9u-fluoro-cortisone-21-caproate, 9u-fluoro-cortisone-2l-pelargonate, 9a-fluoro-cortisone-2l-cyclopentylpropionate, 9afluoro-cortisoue-2l-hexahydrobenzoate, and 9u-fluoro-cortis'one-2l-benzoate.

When reacting the above starting materials with a hydrazide of the formula RNHNH the corresponding hydrazones are obtained:

3-hydrazones-desoxycorticosterone-Zl-esters, such as,

3-benzilic acid hydrazone-desoxycorticosterone-Z1- enanthate and 3-mandelic acid hydrazone-desoxycorticosterone-2l-trimethylacetate; V

3-hydrazones-cortisone-21-esters, such as 3-benzilic acid hydrazonecortisone-2l-butyrate,

3-mandelic acid hydrazone-cortisone-ZI-enanthate,

S-phenylacetic acid hydrazone-cortisone-2l-pelargonate,

3-diphenylacetic acid hydrazone-cortisone-Zl-hexahydrobenzoate,

S-benzilic acid hydrazone-cortisone-Zl-benzoate;

3-hydrazones-hydrocortisone-Zl-esters such as 3-benzilic acid, hydrazone-hydrocortisone-2l-enanthate,

3-mandelic acid hydrazone-hydrocortisone-2l-hexahydrobenzoate,

S-phenylacetic acid hydrazone-hydrocortisone-21-benzoate and derivatives thereof, such as,

S-benzilic acid hydrazone-9a-fluoro-hydrocortisone-Z1- acetate,

3-mandelic acid hydrazone-9u-fluoro-hydrocortisone- ZI-butyrate,

3-phenylacetic acid hydrazone-9u-fluoro-hydrocortisone- 2l-cyclohexy1forrnate,

3-diphenyl-acetic acid hydrazone-9a-fluoro-hydrocortisone-21-enanthate,

3-benzilic acid hydrazone-9u-fiuoro-hydrocortisone-21- benzoate; and

3benzilic acid hydrazone-9ot-fluoro-cortisone-2l-propionate,

3-mandelic acid hydrazone-9a-fluoro-cortisone-2l-caproate,

3-pheny1acetic acid hydrazone-9'u-fluoro-cortisone-21- pelargonate,

3-diphenylacetic acid hydrazone 9ot-fluoro-cortisone-21- cyclopentylpropionate,

S-benzilic acid hydrazone-9a-fiuoro-coItisohe-Zl-hexahydrobenzoate and S-mandelic acid hydrazone-9a-fiuoro-cortisone-2l-benzoate.

As an example of suitable starting compounds for obtaining the hydrazones of group V, there may be mentioned l7a-alkynyl-17-hydroxy esters of A -estrene-3- one, for example,

17a-ethinyl-17 -propionate-A -estrene-3-one, 17u-ethinyl-17-hexahydrobenzoate-A -estrene-3-one, 17 u-ethiny1-17 -benzoate-A -estrene-3-one,

17 et-propargy1-17 -acetate-A -estrene-3-one, 17u-propargyl-17-enanthate-A -estrene-3-one, 17et-propargyl-17-pe1argonate-A -estrene-3-one,

17ot-propargyh17-cyclohexylformate-A -estrene-3 -one, 17a-propargyl- 17 -benzoate-A -estrene-3 -one.

When reacting the above starting materials with a hydrazide of the formula RNHNH the corresponding hydrazones are obtained: the 17a-alkynyl-17-hydroxy esters of A -estrene-3-acid hydrazones, for example,

17u-ethinyl-17-propionate-A -estrene-Ii-benzilic acid hydrazone, 17a-ethinyl-17-hexahydrobenzoate-A -estrene-3- mandelic acid hydrazone, 17a-ethinyl-17-benzoate-A -estrene-3-phenylacetic acid hydrazone, 17u-propargyl-17-acetate-A -estrene-3-diphenylacetic acid hydrazone, 17a-propargyl-17-enanthate-A -estrene-3-benzi1ic acid hydrazone, l7u-propargyl-17-pelargonate-A -estrene-3-mande1ic acid hydrazone, l7a-propargyl-17-cyclohexylformate-A -estrene-3- phenylacetic acid hydrazone, 17a-propargyll7-benzoate-A estrene-3-diphenylacetic acid hydrazone.

As an example of suitable starting compounds for obtaining the hydrazones of group VI, there may be mentioned estrone-3-esters such as,

estrone-3-propionate, estrone-3-enanthate, estrone-3-benzoate, estrone-3-cyclohexylpropionate, estrone-3-hexahydrobenzo ate, estrone-S-trimethylacetate.

When reacting the above starting materials with a hydrazide of the formula RNHNH the corresponding hydrazones are obtained: the 17-hydrazones-estrone-3- esters such as 17-benzilic acid hydrazone-estrone-3-propionate,

17-mandelic acid hydrazone-estrone-3-enanthate,

17-phenylacetic acid hydrazone-estrone-S-benzoate,

17-diphenylacetic acid hydrazone-estrone-3-cyclohexylpropionate,

17-benzilic acid hydrazone-estrone-3-hexahydrobenzoate and 17-mandelic acid hydrazone-estrone-3-trimethylacetate.

The acyl radical R is an acyl radical of a monocarboxylic acid of aliphatic monocarboxylic acids containing from two to ten carbon atoms, for example, acetate, propionate, b-utyrate, isobutyrate, trimethylacetate, valerianate, isovalerianate, caproate, enanthate; cycloaliphatic monocarboxylic acids, for example, fl-cyclopentylpropionate, cyclopentylformate, cyclohexylformate, hexahydrobenzoate, cyclopentylacetate, cyclobutylformate, a-cyclopentylpropionate, cyclohexylacetate, cyclopropylformate, cycloheptylformate, fl-(methylcyclopentyl)-acetate, flmethylcyclopentyl) -propionate, fldimethylcyclopentyl)-propionate, fl-cyclobutylpropionate, and other cycloalkanoates; and benzoate.

It is also possible that in the case of steroids having two or more active hydroxyl groups to use as starting materials, the corresponding dior tri-esters.

Similarly, in the case of steroids having more than one reactive keto group, for example, 17a-esters of hydroxy progesterone, there may be obtained the corresponding dihydrazone.

As an example of suitable hydrazides which can be used, there may be mentioned benzilic acid hydrazide, mandelic acid hydrazide, phenyl-acetic acid hydrazide and diphenylacetic acid hydrazide and other related hydrazides.

The reaction is carried out in a suitable indifferent solvent, i.e. one which is of neutral reaction with the starting hydrazide. It is advisable to add to the reaction mixture a small amount of an organic acid, for example, acetic acid, which has a catalytic eifect upon the reaction and accelerates the same. l If desired, the reaction of the steroid ester with the hyrazide can be carried out in the presence of pure acetic acid, i.e. without any indifferent solvent. The reaction takes place in the cold, after a more or less prolonged contact of the reaction components or by heating the reaction mixture under reflux.

As an example of the long-acting activity of the hydrazones of the present invention, it has been found that in comparison with the already known testosterone-17- enanthate, the 3-benzilic acid hydrazone derivative thereof shows a striking and surprisingly prolonged activity. The measure of the duration of action is obtained by following the change in weight of seminal vesicles and prostate of young castrated rats after a single injection of 32 mg. of the 3-benzilic acid hydrazone-testosterone-17- enanthate, which contains the same amount of testosterone (14.4 mg.) as 20 mg. of testosterone-l7-enanthate. Similar results have also been found with 17-benzilic acid hydrazone-estrone-3-enanthate. In this test, ovariectomized rats are given the estrone-3-enanthate and the 17- benzilic acid hydrazone estrone-3-enanthate in doses equivalent to 500 'y of estrone per rat. Vaginal smears are made at repeated intervals and the presence of oestrus is determined by microscopic examination of the epithelial cells of the vagina. Further 17-enanthate-progesterone-3- benzilic acid hydrazone showed prolonged progestational activity. A single 10 mg. injection was as eflective as repeated daily 1 mg. injections of progesterone in suppressing corpora lutea formation in immature female rats treated with a preliminary dose of oestradiol valerate.

The accompanying drawings show a graphical representation of such tests wherein:

FIGURE 1 shows the change in weight of the prostates, over a period of 16 weeks using testosterone-17-enanthate and 3-benzilic acid hydrazone-testosterone-17-enanthate.

FIGURE 2 shows the changes in weight of the seminal vesicles for the same period when using the same testosterone derivatives,

FIGURE 3 shows the duration of oestrus over a period of 20 weeks using 17 benzilic acid hydrazone-estrone-3- enanthate and estrone-3-enanthate.

When the two sets of curves of FIGURES 1 and 2 are compared, it can be seen that the eiiect of testosterone enanthate is maximal at about 4 weeks and then declines, whereas, from the sixth to the twelfth weeks, equally high or higher weight increases are obtained and maintained with 3-benzilic acid hydrazone-testosterone-l7- enanthate. In the curves of FIGURE 3, it is seen that oestrus is produced with estrone-3-enanthate in of the animals within four days, and that 50% of the animals were still in soestrus at eight weeks. The 17-benzilic acid hydrazone-estrone-3-enanthate also produced oestrus in 100% of the animals in four days, but the duration of oestrus was prolonged and 50% of the animals were still in oestrus at twelve weeks.

The 3-benzilic acid hydrazone-testosterone-l7-enanthate, testosterone-17-enanthate were administered by intramuscular injection in a vegetable oil, such as corn oil and oestrone-3-enanthate and 17 benzilic acid hydrazone-estrone-3-enanthate were administered subcutaneously in a vegetable oil, such as corn oil.

The following examples illustrate a process for the manufacture of steroid hydrazones of the present invention.

EXAMPLE 1 3-Benzilic Acid Hydrazone-Testosterone-J7-Enanthale 5.0 g. of testosterone-17-enanthate and 3.1 g. of benzilic acid hydrazide are heated under reflux for 2. hours in cc. of methanol and 1 cc. of glacial acetic acid. The solvents are removed by distillation and the residue is 9 crystallized from a mixture of isopropyland diethyl ethers.

M.P. 108-110" C. -[ot] +156.0 (ethanol).

EXAMPLE 2 3-Benzilic Acid Hydrazone-Testosterone-I7-Propi0nate 2.0 g. of testosterone-17-propionate and 1.7 g. of benzilic acid hydrazide are heated under reflux for two hours in 50 cc. of methanol and 0.4 cc. of glacial acetic acid. The solvents are removed by distillation, and the residue is crystallized from a mixture of isopropyland diethylethers.

M.P. 132135 C.

[a] +141.5 (ethanol).

EXAMPLE 3 3Mandelic Acid HydrazOne-Testosterone-J7-Enanthate EXAMPLE 4 3-Benzilic Acid Hydrazone-Testosterone-I7-Benzoate 1.5 g. of testosterone-l7-benzoate and 0.93 g. of benzilic acid hydrazide are heated under reflux for 2 hours in 40 cc. of methanol and 0.3 cc. of glacial acetic acid. The solvents are removed by distillation and the residue is crystallized from a mixture .of diethyl ether and nhexane.

M.P. 146-148 C.

[a], +215.8 (ethanol).

EXAMPLE 5 3-Phenylacetic Acid Hydrazone-Testosterone- 1 7-Pr0pi0nate 1.5 g. of testosterone-17-propionate and 0.7 g. of phenylacetic acid hydrazide are dissolved in 37 cc. of methanol and 0.3 cc. of glacial acetic acid and refluxed for 2 hours. The solvents are removed by distillation and the residue is crystallized from a mixture of methanol and isopropyl ether.

M.P. 130-l33 C. [a] +141.5 (ethanol).

EXAMPLE 6 3-Dz'phenylacetic Acid Hydrazone-Testosterone- 1 7-Enanthate 1.6 g. of testosterone-17-enanthate and 1.0 g. of diphenylacetic acid hydrazide are dissolved in 42 cc. of methanol and 0.32 cc. of glacial acetic acid and refluxed for 2 hours. The product crystallizes directly from the reaction mixture.

M.P. 209-211 C.

[oc] +181.9 (chloroform).

EXAMPLE 7 3-Mandelic Acid Hydrazone Test0ster0ne-17-Cycl0- hexylpropionate 1.5 g. of testosterone-l7-cyclohexylpropionate and 0.6 g. of mandelic acid hydrazide are dissolved in 36 cc. of methanol and 0.3 cc. of glacial acetic acid and refluxed .for 2 hours. After removal of solvents the residue is crystallized from ether-hexane.

M.P. 17918l C. [ah +150.8 (ethanol).

.10 EXAMPLE 8 3-Phenylacetic Acid Hydrazone-Testosterone-l7-Benz0ate 1.5 g. of testosterone-17-benzoate and 0.7 g. of phenylacetic acid hydrazide are refluxed for 2 hours in 37 cc. of methanol, 10 cc. of benzene and 0.3 cc. of glacial acetic acid. After removal of the solvent the product is obtained as an amorphous solid.

M.P. 115-119 C.

[111 +2213 (chloroform).

EXAMPLE 9 3-Diphenylacetic Acid Hydrazone Testosterone-17- Benzoate 1.5 g. of testosterone-17-benzoate and 0.87 g. of diphenylacetic acid hydrazide are refluxed for 2 hours in 39 cc. of methanol, 10 cc. of benzene and 0.3 cc. of glacial acetic acid. After removal of the solvent, the product is obtained as an amorphous solid.

M.P. 138-144 C.

[11] +208.9 (chloroform).

EXAMPLE l0 S-Diphenylacetic Acid Hydrazone-Testosterone-l7- Propionate 0.9 g. of testosterone-l7-propionate and 0.6 g. of diphenylacetic acid hydrazide are refluxed for 2 hours in 25 cc. of methanol and 0.2 cc. of glacial acetic acid. The product crystallizes from methanol.

M.P. 242-247 C.

[@1 +186.9 (chloroform).

EXAMPLE 11 S-Benzilic Acid Hydrazone-Testosterone-I7-Cycl0- hexylpropionate 1.4 g. of testosterone-17-cyclohexylpropionate and 0.8 g. of benzilic acid hydrazide are dissolved in 36 cc. of methanol and 0.3 cc. of glacial acetic acid and refluxed for 2 hours. After distillation of the solvent, the product is obtained as an amorphous solid.

M.P. 8790.0 C.

[oc] +141.1 (ethanol).

EXAMPLE 12 3-Benzilic Acid Hydrazone-I9-N0rtest0sterone-17- Propionate 1.2 g. of 19-nortestosterone-17-propionate and 0.8 g. of benzilic acid hydrazide are dissolved in 32 cc. of methanol and 0.24 cc. of glacial acetic acid and refluxed for 2 hours. After removal of the solvent, the product is obtained as an amorphous solid.

M.P. 103-107" C. [04],; +101.0 (ethanol).

EXAMPLE 13 17-Benzilic Acid Hydrazone-Estrone-S-Enanthate 3.0 g. of estrone-3-enanthate and 2.0 g. of benzilic acid hydrazide are heated under reflux for 2 hours in cc. of methanol and 0.6 cc. of glacial acetic acid. The solvents are removed by distillation and the residue is crystallized from a mixture of isopropyland diethyl-ethers.

M.P. 104106 C.

[05], +72.5 (dioxane).

EXAMPLE 14 17-Benzilic Acid Hydrazone-Estr0ne-3-Benzoate 1.5 g. of estrone-3-benzoate and 0.98 g. of benzilic acid hydrazide are heated under reflux for 2 hours in 40 cc. of methanol, 10 cc. of benzene and 0.3 cc. of glacial acetic acid. The solvents are removed by distillation and the residue is crystallized from ethanol.

M.P. 139142 C.

[0:] +85.0 (chloroform).

s aaaea 1 1 EXAMPLE 1s 17-Mandelic Acid Hydrazone-Estrne-3-Prapi0nate 1.0 g. of estrone-3-propionate and 0.55 g. of mandelic acid hydrazide are refluxed for 2 hours in 26 cc. of methanol and 0.2 cc. of glacial acetic acid. After distillation of the solvent, the product is obtained as an amorphous solid.

M.P. 85-103 C.

[0:1 +72.0 (ethanol).

EXAMPLE 16 17-Mandelic Acid Hy drazon e-EstrOne-3-Benz0ate 1.0 g. of estrone-3-benzoate and 0.5 g. of mandelic acid hydrazide are refluxed for 2 hours in 25 cc. of methanol and 0.2 cc. glacial acetic acid. After removal of the solvents, the product is crystallized from aqueous methanol.

M.P. 137143 C.

[@1 +57.1 (chloroform).

EXAMPLE l7 17-Phenylacetic Acid Hydrazone-Estrone-3-Cyclohexylpropionate 1.0 g. of estrone-3-cyclohexylpropionate and 0.45 g. of phenylacetic acid hydrazide are dissolved in 25 cc. of methanol and 0.2 cc. of glacial acetic acid and refluxed for 2 hours. The product crystallizes from methanol.

M.P. 190-193 C.

[a] +21.6 (chloroform).

EXAMPLE 18 17-Diphenylacetic Acid Hydrazone-Estrone-3-Cyclohexylpropionate 1.0 g. of estrone-3-cyclohexylpropionate and 0.55 g. of diphenylacetic acid hydrazide are dissolved in 25 cc. of methanol and 0.2 cc. of glacial acetic acid' and refluxed for 2 hours. The product crystallizes from methanol.

M.P. 203206 C.

[@1 +48.6 (chloroform).

EXAMPLE 19 17-Benzilic Acid Hydraz0ne-Estrone-3-Cyclohexylpropionate 1.5 g. of estrone-3-cyclohexylpropionate and 0.65 g. of benzilic acid hydrazide are dissolved in 36.5 of methanol and 0.3 cc. of glacial acetic acid and refluxed for 2 hours. After removal of the solvents, the product is crystallized from a mixture of isopropyland diethylethers.

M.P. 148149 C.

[a] +56.6 (chloroform).

EXAMPLE 20 17-Phenylacetic Acid Hydrazone-Estrone-3-Enanthate 1.0 g. of estrone-3-enanthate and 0.4 g. of phenylacetic acid hydrazide are dissolved in 24 cc. of methanol and 0.2 cc. of glacial acetic acid and refluxed for 2 hours. The product crystallizes from methanol.

M.P. 168-174 C.

[a] +45.6 (chloroform).

EXAMPLE 21 17-Diphenylacetic Acid Hydrazone-Estrone-3-Propionate 1.0 g. of estrone-3-propionate and 0.7 g. of diphenylacetic acid hydrazide are dissolved in 27 cc. of methanol and 0.2 cc. of glacial acetic acid and refluxed for 2 hours. After removal of the solvent, the product is crystallized from a mixture of benzene and methanol.

M.P. 133-135 C.

[@1 +58.5 (chloroform).

1.2 EXAMPLE 22 .i-Benzilic Acid H ydrazone-Progesterone-l 7 -Pr0pi0nate 0.5 g. of progesterone-17-propionate and 0.32 g. of benzilic acid hydrazide are refluxed for 2 hours in 14 cc. of methanol and 0.1 cc. of glacial acetic acid. After removal of the solvent, the product is obtained from aqueous methanol.

M.P. -147 C.

[M +138.2 (ethanol).

EXAMPLE 23 3-Benzilic Acid Hydmzone-Progesterone-J7-Enanthate 0.5 g. of progesterone-17-enanthate and 0.28 g. of benzilic acid hydrazide are refluxed for 2 hours in 13 cc. of methanol and 0.1 cc. of glacial acetic acid. After removal of the solvent, the product is obtained from aqueous methanol.

M.P. 89-101 C.

[04], +112.3 (chloroform).

EXAMPLE 24 3 -Benzilic A cid H ydrazone-T estosterone-I 7oi-Ethinyl-1 7 Propionate 0.5 g. of testosterone-17u-etl1inyl-17-propionate and 0.33 g. of benzilic acid hydrazide are refluxed for 2 hours in 15 cc. of methanol and 0.1 cc. of glacial acetic acid. After removal of the solvent, the product is crystallized from a mixture of isopropyland diethyl-ethers.

M.P. 149152 C.

[a] +943 (ethanol).

EXAMPLE 25 3-Benzilic Acid H ydrazone-Testoslerone-J 7 a-Ethinyl-J 7- Enanthate 0.5 g. of testosterone-17oi-ethinyl-17-enanthate and 0.28 g. of benzilic acid hydrazide are refluxed for 2 hours in 13 cc. of methanol and 0.1 cc. of glacial acetic acid. After removal of the solvent, the product is crystallized from a mixture of isopropyland diethyl-ethers.

M.P. 138-140 C.

[ab +97.6 (ethanol).

EXAMPLE 26 3-Benzilic Acid Hydrazone-Desoxycorticosterone-ZI- Acetate 2.0 g. of desoxycorticosterone-Zl-acetate and 1.6 g. of benzilic acid hydrazide are refluxed for 2 hours in 56 cc. of methanol and 0.4 cc. of glacial acetic acid. After removal of the solvent, the product is crystallized from methanol.

M.P. 133-136" C.

[061]) +202 (ethanol).

EXAMPLE 27 S-Benzilz'c Acid Hydrazone-Desoxycorticosterone-Zl- Enanthate in order to impart prolonged estrone activity the compound estr0ne-3-enanthate-17-benzilic acid hydrazone.

3. A method comprising administering to an animal in order to impart prolonged testosterone activity testosterone-17-alkanoate-3-benzilic acid hydrazone where the alkanoic acid is a monoalkanoic acid having 2 to 10 carbon atoms.

4. A method comprising administering to an animal in order to impart prolonged estrone activity estrone-l7- alkanoate-3-benzilic acid hydrazone where the alkanoic acid is a monoalkanoic acid having 2 to 10 carbon atoms.

References Cited in the file of this patent UNITED STATES PATENTS Buck et a1 May 18, Levin et al May 17, Velluz June 5, Johnson May 21, Poctsch July 30, Velluz Apr. 7, Cook Sept. 20, 

1. A METHOD COMPRISING ADMINISTERING TO AN ANIMAL IN ORDER TO IMPART PROLONGED TESTOSERONE ACTIVITY THE COMPOUND TESTOSTERONE-17-ENANTHATE-3 BENZILIC ACID HYDRAZONE. 